This invention relates to treatment of anorexia and related states.
Anorexia, defined as the lack or the loss of appetite for food (Dorland's Illustrated Medical Dictionary, 24 edition, W. B. Saunders Company, Philadelphia, 1965) has multiple etiologies. It is commonly associated with cachexia, "a profound and marked state of constitutional disorder, general ill health and malnutrition" [idem]. Common examples of conditions associated with anorexia and cachexia are anorexia nervosa, certain infectious diseases, and malignancy.
Anorexia nervosa is a serious psychiatric disorder affecting predominantly women (94-96%) in the 13-30 age range. Between 1% (Crisp et al., 128 Br. J. Psychiatry 549, 1976) and 3% (Ballot et al., 59 S.Afr. Med. J. 992, 1981) of young women may be affected. The morbidity and mortality from this condition are considerable. Two years from diagnosis, 4-6% have died and only 50% have achieved a normal weight. There are multiple endocrine and metabolic abnormalities present, most of which are believed to be secondary to the malnutrition. A serious complication of the condition is osteoporosis, which can involve both the spine and peripheral bones. At present there is no specific treatment for anorexia nervosa, although multiple approaches have been tried (Piazza, Piazza & Rollins Compr. Psychiatry 21:177-189 1980).
In experimental animals, infection with various agents such as Mycobacterium bovis (Carswell: et al. Proc. Natl. Acad. Sci. U.S.A. 73:3666-3670 1975) caused the appearance of a blood factor that caused necrosis of tumors in mice (tumor necrosis factor, TNF). In a different line of investigation, an agent produced in response to infection with Trypanosoma brucei produced unexpected weight loss an wasting (Rouzer & Cerami Mol. Biochem. Parasitol 2:31-38 1980), and was termed cachexin. TNF and cachexin have since been shown to be the same 17kD protein, produced by activated macrophages. It stimulates several aspects of the immune response. Injected into animals, it produces many of the features of cachexia, including anorexia, bone resorption, and the inhibition of fat uptake into adipocytes. It has been proposed that this agent, which might be produced by tumor cells, or as a host response, could account for some of the cachexia of cancer (Cerami et al. Recent Prog. Horm. Res. 43:99-112 1987). However, the association of cachexin/TNF with malignancy is the subject of conflicting reports.
Nutritional support via either enteral (via the gut) or parenteral (e.g., intravenous) therapy is indicated in patients unable to take sufficient nutrition by mouth, and who are therefore at risk for the complication of malnutrition. Therapy attempts to maintain anabolism (buildup of body substance stores) and avert catabolism (breakdown). To this end, insulin is commonly added to intravenously infused nutrients. Examples of patients requiring parenteral nutrition or other nutritional support include those with inflammatory bowel diseases, patients with resected bowel, severe preoperative malnutrition and acute pancreatitis (Howard, In: Harrison's Principals of Internal Medicine 12th Edition, Wilson et al. (eds) McGraw-Hill, N.Y. 1991, p. 429).
Human diabetics are deficient in insulin secretion, and in some cases lack insulin. Insulin is one of several hormones which play a role in regulation of blood glucose levels. Simplistically, there are two main stores of glucose in a mammal--the liver and skeletal muscle, where glucose is stored in the form of glycogen. Muscle glycogen is used as a glucose source for the muscle, whereas liver glycogen is used as a glucose source for all tissues, including blood. It is the interplay of certain hormones in regulation of glycogen accumulation and breakdown that is critical in the invention described below.
Insulin regulates glucose uptake by muscle tissue for storage of the glucose as muscle glycogen. Insulin also prevents hyperglycemia, that is, the unacceptable accumulation of high levels of glucose in the blood, and suppresses conversion of liver glycogen to glucose, and subsequent secretion of that glucose into the blood. In the presence of excess insulin, blood glucose accumulates in muscle tissue as glycogen, liver glucose output is suppressed, and the level of blood glucose falls, to create a condition termed hypoglycemia.
Another hormone, glucagon, increases blood glucose levels by stimulating liver glycogen breakdown to glucose, and subsequent secretion of that glucose. This liver glycogen is used to maintain blood glucose levels, and glucagon may be considered an insulin counterregulatory hormone.
Amylin is another hormone which has been discovered to be concerned in regulation of blood glucose levels. It reverses insulin-mediated suppression of liver glucose output in rats. Molina et al., 39 Diabetes 260, 1990, and Koopmans et al., 39 Diabetes 101A, 1990.
European Patent Application No. 88307927.9 describes the treatment of diabetes mellitus or hypoglycemia with amylin, or with a combination of amylin and insulin, preferably at a ratio of between 100:1 to 0.1:1 insulin to amylin.